Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/37—Esters of carboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/194—Carboxylic acids, e.g. valproic acid having two or more carboxyl groups, e.g. succinic, maleic or phthalic acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
  • A61K31/225—Polycarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K8/00—Cosmetics or similar toiletry preparations
  • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
  • A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
  • A61K8/33—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing oxygen
  • A61K8/36—Carboxylic acids; Salts or anhydrides thereof
  • A61K8/365—Hydroxycarboxylic acids; Ketocarboxylic acids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/10—Dispersions; Emulsions
  • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/02—Preparations for care of the skin for chemically bleaching or whitening the skin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
  • A61Q19/00—Preparations for care of the skin
  • A61Q19/04—Preparations for care of the skin for chemically tanning the skin
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
  • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
  • C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
  • C07C57/13—Dicarboxylic acids
  • C07C57/15—Fumaric acid
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/02—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters

Definitions

• the present invention relates to the use of dihydroxyfumaric acid derivatives for the lightening of the skin, for the inhibition of tyrosinase and for the prophylaxis, treatment and/or progress control of pigment defects of the skin, and to cosmetic and dermatological preparations and medicaments comprising dihydroxyfumaric acid derivatives and to novel dihydroxyfumaric acid derivatives.
• Skin and hair colour are dependent on the content, size, distribution and type of the nitrogen-containing, dark dye melanin, which is produced in the cells which are capable of melanin formation (melanocytes).
• melanocytes which are produced in the cells which are capable of melanin formation.
• melanocyte-specific enzymes such as, for example, tyrosinase or tyrosinase-related proteins
• melanin is synthesised within the melanocytes.
• the melanin is subsequently transferred to the keratinocytes in the form of so-called melanosomes.
• the melanin in the skin represents suitable protection against UV radiation, darker or overpigmented skin may affect beauty and result in serious aesthetic problems.
• Hyperpigmented skin areas or lesions contain melasma (also known as chloasma), i.e. yellowish-brown spots of irregular shape.
• freckles ephelides
• age spots lentigines
• age warts verrucae seborrhoica
• hyperpigmentation for example chloasma or melasma
• people of skin type I i.e. with very pale skin and reddish hair
• hyperpigmentation chloasma
• women of skin type I i.e. with very pale skin and reddish hair
• hyperpigmentation chloasma
• the sun very frequently plays an important role. Prevention can be achieved, in particular, by regular sun protection with a high light protection factor.
• a large number of compounds having a skin-lightening action is available on the market for the treatment of pigment spots.
• compounds such as, for example, kojic acid, arbutin, aloesin, niacinamide, vitamin C or rucinol, which suppress melanin production in the skin.
• Plant extracts such as, for example, from Morus alba or Phyllanthus emblica , are also used to lighten the skin tint, especially in south-east Asia. This can take place utilising various mechanisms.
• skin-lightening substances usually delay the conversion of tyrosine into melanin by blocking the enzyme tyrosinase.
• the invention is based on the object of overcoming the disadvantages indicated in the prior art and developing effective compounds which have effective capability for skin lightening—with the aim of improving the cosmetic or therapeutic efficacy at the same time as reducing the side effects.
• the present invention therefore relates firstly to the use of at least one compound of the formula (I)
• R1 and R2 are selected, independently of one another, from:
• the present invention furthermore relates to the use of at least one compound of the formula (I) as defined above for the inhibition of tyrosinase.
• the present invention furthermore relates to the use of at least one compound of the formula (I) as defined above for the prophylaxis, treatment and/or progress control of pigment defects of the skin.
• WO 01/66105 A1 describes a skin-lightening formulation consisting of a combination of kojic acid, an antioxidant and a hydroxy acid.
• Dihydroxyfumaric acid is listed here as possible antioxidant or as possible hydroxy acid.
• the skin-lightening action arises, in particular, through the three components present in combination.
• lactic acid and glycolic acid are employed as hydroxy acid.
• a preparation comprising dihydroxyfumaric acid is not disclosed.
• Example 5 of WO 01/66105 A1 it is shown in Example 5 of WO 01/66105 A1 that the hydroxy acid lactic acid alone already has a melanin-reducing action of 40%, but this is worse than the action of the kojic acid derivative (45%).
• dihydroxyfumaric acid alone likewise exhibits a skin-lightening action which exceeds the action of lactic acid, glycolic acid and even kojic acid by a multiple. This is described in the working examples.
• DE 69825501 T2 discloses the use of dihydroxyfumaric acid in comfort strips for razors.
• US 2006/0110415 A1 describes the use of alkyl and aryl esters of dihydroxyfumaric acid for increasing the skin penetration of active compounds. However, the skin-lightening action of dihydroxyfumaric acid derivatives is not disclosed.
• the compounds of the formula (I) and salts thereof simultaneously have valuable cosmetic and/or pharmacological properties while being well tolerated in that the lightening of the skin is accompanied by a relative melanin content of less than 90%, preferably less than 80%, particularly preferably less than 70%.
• the compounds of the formula (I) described are tyrosinase inhibitors and, owing to this property, exhibit the desired activity as skin lightener.
• the invention thus relates to the use of at least one compound of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios, for the inhibition of tyrosinase, preferably also in vitro.
• the term “inhibition” relates to any reduction in the activity which is based on the action of the specific compounds according to the invention in that the latter are capable of interacting with the target molecule in such a way that recognition, bonding and blocking is facilitated.
• the compounds are distinguished by high affinity to tyrosinase, ensuring reliable bonding and preferably complete blocking of the oxidase activity.
• the compounds are particularly preferably monospecific in order to guarantee exclusive and direct recognition of the selected oxidase.
• the term “recognition” here relates to any type of interaction between the compound and the target molecules mentioned, in particular covalent or non-covalent bonding, such as, for example, covalent bonding, hydrophobic/hydrophilic interactions, van der Waals forces, ion attraction, hydrogen bonds or ligand-receptor interactions.
• the above-mentioned use of the compounds can take place in in-vitro or in-vivo models.
• the susceptibility of a particular cell to treatment with the compounds of the formula (I) can be determined by testing in vitro. Typically, a culture of the cell is incubated with a compound according to the invention at various concentrations for a period of time which is sufficient to enable the active agents to inhibit the synthesis of melanin, usually between approximately one hour and one week.
• cultivated cells from a biopsy sample can be used. The amount of melanin remaining in the cells after the treatment is then determined.
• the use in vitro takes place, in particular, on samples of mammal species which are suffering from pigment disorders of the skin.
• the host or patient can belong to any mammal species, for example a primate species, in particular humans, but also rodents (including mice, rats and hamsters), rabbits, horses, cows, dogs, cats, etc. Animal models are of interest for experimental investigations, providing a model for the treatment of a human disease or cosmetic anomaly.
• a primate species in particular humans, but also rodents (including mice, rats and hamsters), rabbits, horses, cows, dogs, cats, etc.
• Animal models are of interest for experimental investigations, providing a model for the treatment of a human disease or cosmetic anomaly.
• the testing of a plurality of specific compounds enables the selection of the active compound which appears the most suitable for the treatment of the patient.
• the in-vivo dose of the selected compound is advantageously matched to the susceptibility of tyrosinase and/or severity of the pigment disorder of the patient taking into account the in-vitro data, as a result of which the therapeutic efficacy is noticeably increased.
• the dose varies depending on the specific compound used, the specific disease, the patient status, etc.
• a cosmetic dose is typically sufficient considerably to reduce the undesired amount of melanin in the target tissue, while the quality of life of the patient is maintained and ultimately improved.
• the use is generally continued until a considerable reduction in the tyrosinase activity and melanin production has occurred, for example at least about 10% reduction of the melanin content, and can be continued until essentially no further undesired overproduction of melanin in the body is detected.
• skin lightening represents a repeated or ongoing treatment, since, after removal of the preparations of the formula (I), the normal melanin synthesis rate is taken up again.
• the compounds according to the invention exhibit and cause an inhibiting effect, which is usually documented by IC 50 values in a suitable range, preferably in the micromolar range and more preferably in the nanomolar range.
• Tyrosinase is, in particular, inhibited to the extent of 50% if the concentration of the compounds is less than 1 ⁇ M, preferably less than 0.5 ⁇ M, particularly preferably less than 0.1 ⁇ M. This concentration is called the IC 50 value.
• compounds of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios are suitable for use in the prophylaxis, therapy and/or progress control of diseases which are caused, promoted and/or spread by tyrosinase activity.
• the use of the compounds of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios, for the prophylaxis, therapy and/or progress control of diseases which are caused, promoted and/or spread by tyrosinase activity is thus also in accordance with the invention.
• the present invention therefore also relates to the use of compounds of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios, for the preparation of a medicament for the prophylaxis, therapy and/or progress control of diseases which are caused, promoted and/or spread by tyrosinase activity.
• suitable models or model systems have been developed, for example cell-culture models (Khwaja et al. (1997) EMBO 16: 2783) and transgenic animal models (White et al. (2001) Oncogene 20: 7064).
• interacting compounds can be used in order to modulate the signal (Stephens et al. (2000) Biochemical J 351: 95).
• the compounds according to the invention can also be used as reagents for testing oxidase-dependent signalling pathways in animals and/or cell-culture models or in the clinical diseases mentioned in this application. As discussed herein, these signalling pathways are relevant for various diseases. Accordingly, the compounds according to the invention are useful in the prophylaxis, therapy and/or progress control of diseases which are dependent on signalling pathways with participation by tyrosinase.
• compounds of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios are suitable for use in the prophylaxis, therapy and/or progress control of pigment disorders selected from the group of hyperpigmentation, freckles, age spots and sun spots.
• the use of the compounds of the formula (I) as defined above can accordingly be of a cosmetic or pharmaceutical, in particular dermatological, nature. It is preferably a cosmetic use, particularly preferably a non-therapeutic cosmetic use.
• a further embodiment of the present invention relates to the use of the compounds of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios, in combination with at least one further active compound, which is preferably selected from the group of antioxidants, vitamins, UV filters, skin-lightening active compounds, self-tanning active compounds, anti-inflammatory agents, antimicrobial active compounds, active compounds which improve the skin moisture content, ageing-inhibiting active compounds (anti-ageing active compounds) and anticellulite active compounds.
• at least one further active compound which is preferably selected from the group of antioxidants, vitamins, UV filters, skin-lightening active compounds, self-tanning active compounds, anti-inflammatory agents, antimicrobial active compounds, active compounds which improve the skin moisture content, ageing-inhibiting active compounds (anti-ageing active compounds) and anticellulite active compounds.
• the compounds of the formula (I) are defined in such a way that they are also taken to mean pharmaceutically or cosmetically usable derivatives, salts, hydrates, solvates, precursors of the compounds and tautomers.
• Solvate of the compounds are taken to mean adductions of inert solvent molecules onto the compounds, which form owing to their mutual attractive force.
• Solvate are, for example, mono- or dihydrates or alcoholates.
• Pharmaceutically or cosmetically usable derivatives are taken to mean, for example, the salts of the compounds according to the invention and so-called precursors of the compounds.
• Precursors are taken to mean, for example, compounds of the formula (I) modified by means of alkyl or acyl groups, sugars or oligopeptides, which are rapidly cleaved in the organism to give the effective compounds according to the invention.
• These also include biodegradable polymer derivatives of the compounds according to the invention, as described, for example, in Int. J. Pharm. 115, 61-67 (1995).
• Any compound which can be converted in vivo into a bioactive agent, i.e. compounds of the formula (I) is a precursor in the sense of this invention.
• Any biologically active compound which results from the in-vivo metabolisation of a compound according to the invention is a metabolite in the sense of the present invention.
• alkyl stands as abbreviation for alkyl group.
• the alkyl radical may be unbranched (straight-chain) or branched.
• An unbranched or branched alkyl having 1 to 8 C atoms is taken to mean, for example, methyl, ethyl, isopropyl, propyl, butyl, sec-butyl or tert-butyl, pentyl, isopentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-, 2-, 3- or 4-methylpentyl, hexyl, heptyl, 2-ethylpentyl, octyl or 2-ethyl hexyl.
• an alkyl radical having 1 to 18 C atoms can be, for example, also nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl or octadecyl.
• Alkenyl stands as abbreviation for alkenyl group, where a plurality of double bonds may also be present.
• a branched or unbranched alkenyl group having 2 to 8 C atoms is, for example, allyl, vinyl, propenyl, 2- or 3-butenyl, isobutenyl, sec-butenyl, 2-methyl-1- or 2-butenyl, 3-methyl-1-butenyl, 1,3-butadienyl, 2-methyl-1,3-butadienyl, 2,3-dimethyl-1,3-butadienyl, 1-, 2-, 3- or 4-pentenyl, isopentenyl, hexenyl, heptenyl or octenyl.
• alkenyl groups having 2 to 18 C atoms are —C 9 H 17 , —C 10 H 19 to —C 18 H 35 .
• Alkynyl stands as abbreviation for alkynyl group, where a plurality of triple bonds may also be present.
• Examples of a branched or unbranched alkynyl group having 2 to 8 C atoms are ethynyl, 1- or 2-propynyl, 2- or 3-butynyl, furthermore 4-pentynyl, 3-pentynyl, hexynyl, heptynyl, octynyl.
• alkynyl groups having 2 to 18 C atoms are —C 9 H 15 , —C 10 H 17 to —C 18 H 33 .
• a cyclic alkyl having 3 to 8 C atoms in the sense of the invention denotes saturated and partially unsaturated non-aromatic cyclic hydrocarbon groups which contain 3 to 8 C atoms and may be unsubstituted or substituted.
• the bonding to the basic structure of the formula (I) can take place via any ring member of the cycloalkyl group.
• suitable cycloalkyl radicals are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl and cyclooctadienyl.
• Examples of mono-, bi- or tricyclic aromatic or heteroaromatic ring systems having 5 to 20 C atoms in the sense of the present invention are phenyl, methylphenyl, 2,6-dimethylphenyl, 3,5-dimethylphenyl, methoxyphenyl, 2,6-dimethoxyphenyl, 3,5-dimethoxyphenyl, 2,4-dimethoxyphenyl, 2,4,6-trimethoxyphenyl, 2,3,4-trimethoxyphenyl, biphenyl, naphthyl, binaphthyl, anthracenyl, phenanthrenyl, pyridinyl, furanoyl or benzofuranoyl.
• R1 and R2 in formula (I) are preferably selected, independently of one another, from:
• R1 and R2 in formula (I) are particularly preferably selected, independently of one another, from:
• R1 and R2 simultaneously stand for H.
• Formula (I) then corresponds to dihydroxyfumaric acid.
• dihydroxyfumaric acid and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios, are used.
• the compounds of the formula (I) and also the starting materials for their preparation are prepared by methods known per se, as are described in the literature (for example in standard works, such as Houben-Weyl, Methoden der organischen Chemie [Methods of Organic Chemistry], Georg-ThiemeVerlag, Stuttgart) and/or are known person skilled in the art, and under reaction conditions which are known and suitable for the said reactions. Use can also be made here of variants known per se which are not mentioned here in greater detail.
• Dihydroxyfumaric acid can be prepared from dl-tartaric acid in the presence of iron ions, for example in accordance with Roumanian Biotechnological Letters 2002, 7(5), 897-904 or Russian Journal of Physical Chemistry 1986, 60(1), 43-46.
• esterification of the carboxylic acid functionalities can be carried out using standard esterification methods which are familiar to the person skilled in the art.
• the starting compounds are generally known. If they are novel, they can be prepared by methods known per se.
• the said compounds according to the invention can be used in their final non-salt form.
• the present invention also encompasses the use of these compounds in the form of their physiologically acceptable salts, which can be derived from various organic and inorganic acids and bases by procedures known in the art.
• physiologically acceptable salt forms of the compounds of the formula (I) are for the most part prepared by conventional methods. If the compounds contain a carboxyl group, one of its suitable salts can be formed by reacting the compound with a suitable base to give the corresponding salt.
• Such bases are, for example, alkali-metal hydroxides (for example potassium hydroxide, sodium hydroxide and lithium hydroxide), alkaline-earth metal hydroxides (for example barium hydroxide and calcium hydroxide), alkali-metal alkoxides (for example potassium ethoxide and sodium propoxide) and various organic bases, such as piperidine, diethanolamine and N-methylglutamine.
• a base of the formula (I) can be converted into the associated acid-addition salt using an acid, for example by reaction of equivalent amounts of the base and the acid in an inert solvent, such as, for example, ethanol, with subsequent evaporation.
• Suitable acids for this reaction are, in particular, those which give physiologically acceptable salts, such as, for example, hydrogen halides (for example hydrogen chloride, hydrogen bromide or hydrogen iodide), other mineral acids and corresponding salts thereof (for example sulfate, nitrate or phosphate and the like), alkyl- and monoarylsulfonates (for example ethanesulfonate, toluenesulfonate and benzenesulfonate) and other organic acids and corresponding salts thereof (for example acetate, trifluoroacetate, tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbate and the like.
• physiologically acceptable salts such as, for example, hydrogen halides (for example hydrogen chloride, hydrogen bromide or hydrogen iodide), other mineral acids and corresponding salts thereof (for example sulfate, nitrate or phosphate and the like), alkyl- and monoarylsul
• the salts in the sense of the invention can be based on the carboxylate groups as are present in the compounds of the formula (I) in that their acidic proton can be replaced by a metal.
• the salts in the sense of the invention can also be based on compounds of the formula (I) in which the proton on the alcohol function of the dihydroxyfumaric acid derivatives has been replaced by an ion.
• This can be monovalent ions, such as, for example, Li + , Na + , K + or NH 4 + , but also polyvalent ions, giving salts of the (dihydroxyfumaric acid derivative) 2 M or (dihydroxyfumaric acid derivative) 3 M 2 etc. type.
• physiologically acceptable salt in the present connection is therefore to be taken to mean an active compound which comprises a compound of the formula (I) in the form of one of its salts, in particular if this salt form imparts improved cosmetic and/or pharmacokinetic properties on the active compound compared with the free form of the active compound.
• the physiologically acceptable salt form of the active compound can also provide this active compound for the first time with a desired cosmetic and/or pharmacokinetic property and can even have a positive influence on the pharmacodynamics of this active compound with respect to its therapeutic efficacy in the body.
• Preferred salts in the sense of the invention are the lithium, sodium, potassium, magnesium, calcium, zinc, copper and ammonium salts of the compounds of the formula (I).
• the present invention furthermore relates to a cosmetic or dermatological preparation comprising at least one compound of the formula (I)
• R1 and R2 are selected, independently of one another, from:
• agent for the purposes of the present invention, the term “agent”, “composition” or “formulation” is also used synonymously alongside the term “preparation”.
• the preparations here are usually preparations which can be applied topically, such as, for example, cosmetic or dermatological formulations or medical products.
• Can be applied topically in the sense of the invention means that the preparation is applied externally and locally, i.e. that the preparation must be suitable, for example, for being able to be applied to the skin.
• the preparations comprise a cosmetically, pharmaceutically or dermatologically suitable vehicle and, depending on the desired property profile, optionally further suitable ingredients.
• the topical preparations are preferably employed as cosmetic or dermatological preparation, particularly preferably as cosmetic preparation. Suitable vehicles and assistants or fillers are described in detail in the following part.
• the preparations may include or comprise, essentially consist of or consist of the necessary or optional constituents mentioned above and/or below. All compounds or components which can be used in the preparations are either known and commercially available or can be synthesised by known processes. Further preferred combinations of embodiments are disclosed in the Claims.
• the compound of the formula (I), as indicated above and also as preferably described, and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios, are present in the preparation of the invention in an amount of 0.0001 to 20% by weight, based on the total weight of the preparation.
• An amount of 0.0001 to 15% by weight is preferably employed, particularly preferably 0.0001 to 10% by weight, very particularly preferably 0.0001 to 5% by weight.
• the person skilled in the art is presented with absolutely no difficulties in selecting appropriately the amounts depending on the intended effect of the preparation.
• the further active compound is preferably selected from the group of UV filters, antioxidants, vitamins, skin-lightening active compounds, anti-ageing active compounds, anti-inflammatory active compounds, antimicrobial active compounds, active compounds for improving the moisture content of the skin (skin-moisture regulators), anticellulite active compounds, antiwrinkle active compounds, antidandruff active compounds, anti-acne active compounds, deodorants, pigments and self-tanning substances, particularly preferably from the group of UV filters, antioxidants, vitamins, skin-lightening active compounds, self-tanning substances, anti-ageing active compounds and anticellulite active compounds.
• Preparations which are preferred in accordance with the invention also comprise one or more UV filters besides at least one compound of the formula (I).
• all UV filters are suitable for combination with the compounds of the formula (I) in the preparation according to the invention.
• Particular preference is given to UV filters whose physiological acceptability has already been demonstrated.
• the compounds shown in the following lists should only be regarded as examples. Other UV filters can of course also be used.
• preferred preparations may comprise organic UV filters, so-called hydrophilic or lipophilic sun-protection filters, which are effective in the UVA region and/or UVB region and/or IR and/or VIS region (absorbers).
• organic UV filters so-called hydrophilic or lipophilic sun-protection filters, which are effective in the UVA region and/or UVB region and/or IR and/or VIS region (absorbers).
• These substances can be selected, in particular, from p-aminobenzoic acid derivatives, salicylic acid derivatives, ⁇ , ⁇ -diphenylacrylate derivatives, camphor derivatives, triazine derivatives, cinnamic acid derivatives and polymeric filters and silicone filters, which are described in the application WO 93/04665.
• Further examples of organic filters are indicated in the patent application EP-A 0 487 404.
• the said UV filters are usually named below in accordance with INCI nomenclature.
• para-Aminobenzoic acid and derivatives thereof PABA, Ethyl PABA, Ethyl dihydroxypropyl PABA, Ethylhexyl dimethyl PABA, for example marketed by ISP under the name “Escalol 507”, Glyceryl PABA, PEG-25 PABA, for example marketed by BASF under the name “Uvinul P25”.
• Salicylates Homosalate marketed by Merck under the name “Eusolex HMS”; Ethylhexyl salicylate, for example marketed by Symrise under the name “Neo Heliopan OS”; Dipropylene glycol salicylate, for example marketed by Scher under the name “Dipsal”; TEA salicylate, for example marketed by Symrise under the name “Neo Heliopan TS”.
• ⁇ , ⁇ -Diphenylacrylate derivatives Octocrylene, for example marketed by Merck under the name “Eusolex® OCR”; “Uvinul N539” from BASF; Etocrylene, for example marketed by BASF under the name “Uvinul N35”.
• Benzophenone derivatives benzophenone-1, for example marketed under the name “Uvinul 400”; benzophenone-2, for example marketed under the name “Uvinul D50”; benzophenone-3 or oxybenzone, for example marketed under the name “Uvinul M40”; benzophenone-4, for example marketed under the name “Uvinul MS40”; benzophenone-9, for example marketed by BASF under the name “Uvinul DS-49”; benzophenone-5, benzophenone-6, for example marketed by Norquay under the name “Helisorb 11”; benzophenone-8, for example marketed by American Cyanamid under the name “Spectra-Sorb UV-24”; benzophenone-12 n-hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate or 2-hydroxy-4-methoxybenzophenone, marketed by Merck, Darmstadt, under the name Eusolex® 4360.
• Benzylidenecamphor derivatives 3-benzylidenecamphor, for example marketed by Chimex under the name “Mexoryl SD”; 4-methylbenzylidenecamphor, for example marketed by Merck under the name “Eusolex 6300”; benzylidenecamphorsulfonic acid, for example marketed by Chimex under the name “Mexoryl SL”; Camphor benzalkonium methosulfate, for example marketed by Chimex under the name “Mexoryl SO”; terephthalylidenedicamphorsulfonic acid, for example marketed by Chimex under the name “Mexoryl SX”; polyacrylamidomethylbenzylidenecamphor marketed by Chimex under the name “Mexoryl SW”.
• Phenylbenzimidazole derivatives phenylbenzimidazolesulfonic acid, for example marketed by Merck under the name “Eusolex 232”; disodium phenyl dibenzimidazole tetrasulfonate, for example marketed by Symrise under the name “Neo Heliopan AP”.
• Phenylbenzotriazole derivatives Drometrizol trisiloxane, for example marketed by Rhodia Chimie under the name “Silatrizole”; Methylenebis(benzotriazolyl)tetramethylbutylphenol in solid form, for example marketed by Fairmount Chemical under the name “MIXXIM BB/100”, or in micronised form as an aqueous dispersion, for example marketed by BASF under the name “Tinosorb M”.
• Triazine derivatives Ethylhexyltriazone, for example marketed by BASF under the name “Uvinul T150”; Diethylhexylbutamidotriazone, for example marketed by Sigma 3V under the name “Uvasorb HEB”; 2,4,6-tris(diisobutyl 4′-aminobenzalmalonate)s-triazine or 2,4,6-Tris(biphenyl)-1,3,5-triazine marketed by BASF as Tinosorb A2B; 2,2′-[6-(4-methoxyphenyl)-1,3,5-triazine-2,4-diyl]bis[5-(2-ethylhexyl)oxy]phenol; marketed by BASF as Tinosorb S; N2,N4-bis[4-[5-(1,1-dimethylpropyl)-2-benzoxazolyl]phenyl]-N6-(2-ethylhexyl
• Anthraniline derivatives Menthyl anthranilate, for example marketed by Symrise under the name “Neo Heliopan MA”.
• Imidazole derivatives ethylhexyldimethoxybenzylidenedioxoimidazoline propionate.
• Benzalmalonate derivatives polyorganosiloxanes containing functional benzalmalonate groups, such as, for example, Polysilicone-15, for example marketed by Hoffmann LaRoche under the name “Parsol SLX”.
• 4,4-Diarylbutadiene derivatives 1,1-Dicarboxy(2,2′-dimethylpropyl)-4,4-diphenylbutadiene.
• Benzoxazole derivatives 2,4-bis[5-(1-dimethylpropyl)benzoxazol-2-yl(4-phenyl) imino]-6-(2-ethylhexyl)imino-1,3,5-triazine, for example marketed by Sigma 3V under the name Uvasorb K2A, and mixtures comprising this.
• Piperazine derivatives such as, for example, the compound
• Suitable organic UV-protecting substances can preferably be selected from the following list: Ethylhexyl salicylate, phenylbenzimidazolesulfonic acid, benzophenone-3, benzophenone-4, benzophenone-5, n-Hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate, 4-methylbenzylidenecamphor, terephthalylidenedicamphorsulfonic acid, disodium phenyldibenzimidazoletetrasulfonate, methylenebis(benzotriazolyl)tetramethylbutylphenol, Ethylhexyltriazone, Diethylhexylbutamidotriazone, Drometrizole trisiloxane, Polysilicone-15,1,1-Dicarboxy(2,2′-dimethylpropyl)-4,4-diphenylbutadiene, 2,4-Bis[5-1 (dimethylpropyl
• organic UV filters are generally incorporated into formulations in an amount of 0.01 to 20 percent by weight, preferably 1 to 20% by weight.
• the preparations may comprise further inorganic UV filters, so-called particulate UV filters.
• particulate UV filters are possible both as powder and also as dispersion or paste of the following types.
• coated titanium dioxide for example Eusolex® T-2000, Eusolex® T-AQUA, Eusolex® T-AVO, Eusolex® T-OLEO
• zinc oxides for example Sachtotec®
• iron oxides or also cerium oxides and/or zirconium oxides for example Hombitan® FG or Hombitan® FF-Pharma.
• the preparations may furthermore be preferred for the preparations to comprise inorganic UV filters which have been aftertreated by conventional methods, as described, for example, in Cosmetics & Toiletries 1990, 105, 53.
• One or more of the following aftertreatment components can be selected here: amino acids, beeswax, fatty acids, fatty acid alcohols, anionic surfactants, lecithin, phospholipids, sodium, potassium, zinc, iron or aluminium salts of fatty acids, polyethylenes, silicones, proteins (particularly collagen or elastin), alkanolamines, silicon dioxide, aluminium oxide, further metal oxides, phosphates, such as sodium hexametaphosphate, or glycerine.
• Particulate UV filters which are preferably employed here are:
• the treated micronised titanium dioxides employed for the combination may also be aftertreated with:
• mixtures of various metal oxides such as, for example, titanium dioxide and cerium oxide
• aftertreatment such as, for example, the product Sunveil A from Ikeda
• mixtures of aluminium oxide-, silicon dioxide- and silicone-aftertreated titanium dioxide/zinc oxide mixtures such as, for example, the product UV-Titan M261 from Sachtleben, can also be employed.
• inorganic UV filters are generally incorporated into the preparations in an amount of 0.1 to 25 percent by weight, preferably 2 to 10% by weight.
• the protective action against harmful effects of the UV radiation can be optimised.
• All said UV filters can also be employed in encapsulated form.
• the capsules in preparations to be employed in accordance with the invention are preferably present in amounts which ensure that the encapsulated UV filters are present in the preparation in the percent by weight ratios indicated above.
• a further preferred embodiment of the invention relates to the combination of the compounds of the formula (I) with at least one substance which serves for maintaining and/or improving the moisture content of the skin.
• These substances can, without this being intended to be regarded as a restriction, also be, inter alia, substances which belong to the so-called natural moisturising factors, such as, for example, 2-oxopyrrolidine 5-carboxylic acid.
• the preparation comprises one or more antioxidants and/or one or more vitamins.
• antioxidants enables a protective action against oxidative stress or against the effect of free radicals in general to be achieved, the person skilled in the art being presented with absolutely no difficulties in selecting antioxidants which act suitably quickly or with a time delay.
• antioxidants for example amino acids (for example glycine, histidine, tyrosine, tryptophan) and derivatives thereof, imidazoles, (for example urocanic acid) and derivatives thereof, peptides, such as, for example, D,L-carnosine, D-carnosine, L-carnosine and derivatives thereof (for example anserine), carotinoids, carotenes (such as, for example, ⁇ -carotene, ⁇ -carotene, lycopene) and derivatives thereof, chlorogenic acid and derivatives thereof, lipoic acid and derivatives thereof (such as, for example, dihydrolipoic acid), aurothioglucose, propylthiouracil and other thiols (such as, for example, thioredoxin, glutathione, cysteine, cystine, cystamine and the glycosyl, N-acetyl, methyl,
• Suitable antioxidants are also compounds of the general formulae A or B
• derivatives of 2-(4-hydroxy-3,5-dimethoxybenzylidene)malonic acid and/or 2-(4-hydroxy-3,5-dimethoxybenzyl)malonic acid particularly preferably bis(2-ethylhexyl) 2-(4-hydroxy-3,5-dimethoxybenzylidene)malonate (for example Oxynex® ST Liquid) and/or bis(2-ethylhexyl) 2-(4-hydroxy-3,5-dimethoxybenzy)malonate (for example RonaCare® AP).
• antioxidants are likewise suitable for use in the preparations according to the invention.
• Known and commercial mixtures are, for example, mixtures comprising, as active ingredients, lecithin, L-(+)-ascorbyl palmitate and citric acid, natural tocopherols, L-(+)-ascorbyl palmitate, L-(+)-ascorbic acid and citric acid (such as, for example, Oxynex® K LIQUID), tocopherol extracts from natural sources, L-(+)-ascorbyl palmitate, L-(+)-ascorbic acid and citric acid (such as, for example, Oxynex® L LIQUID), DL- ⁇ -tocopherol, L-(+)-ascorbyl palmitate, citric acid and lecithin (such as, for example, Oxynex® LM) or butylhydroxytoluene (BHT), L-(+)ascorbyl palmitate and citric acid (such as, for example
• the polyphenols are of particular interest for applications in the pharmaceutical, cosmetic or nutrition sector.
• the flavonoids or bioflavonoids which are principally known as plant dyes, frequently have an antioxidant potential.
• Lemanska et al. Current Topics in Biophysics 2000, 24(2), 101-108, are concerned with effects of the substitution pattern of mono- and dihydroxyflavones. It is observed therein that dihydroxyflavones containing an OH group adjacent to the keto function or OH groups in the 3′4′- or 6,7- or 7,8-position have antioxidative properties, while other mono- and dihydroxyflavones in some cases do not have antioxidative properties.
• Quercetin (cyanidanol, cyanidenolon 1522, meletin, sophoretin, ericin, 3,3′,4′,5,7-pentahydroxyflavone) is frequently mentioned as a particularly effective antioxidant (for example Rice-Evans et al., Trends in Plant Science 1997, 2(4), 152-159). Lemanska et al., Free Radical Biology & Medicine 2001, 31(7), 869-881, have investigated the pH dependence of the antioxidant action of hydroxyflavones. Quercetin exhibits the highest activity amongst the structures investigated over the entire pH range.
• the preparations according to the invention may comprise vitamins as further ingredients.
• Vitamins and vitamin derivatives selected from vitamin A, vitamin A propionate, vitamin A palmitate, vitamin A acetate, retinol, vitamin B, thiamine chloride hydrochloride (vitamin B 1 ), riboflavin (vitamin B 2 ), nicotinamide, vitamin C (ascorbic acid), vitamin D, ergocalciferol (vitamin D 2 ), vitamin E, DL- ⁇ -tocopherol, tocopherol E acetate, tocopherol hydrogensuccinate, vitamin K1, esculin (vitamin P active compound), thiamine (vitamin B 1 ), nicotinic acid (niacin), pyridoxine, pyridoxal, pyridoxamine, (vitamin B 6 ), panthothenic acid, biotin, folic acid and cobalamine (vitamin B 12 ) are preferably present in the preparations according to the invention, particularly preferably vitamin A palmitate,
• the preparations according to the invention also comprise one or more further skin-lightening active compounds (or synonymously depigmentation active compounds) or extracts having a skin-lightening activity.
• Skin-lightening active compounds can in principle be all active compounds known to the person skilled in the art. Suitable for combination are commercially available melanogenesis inhibitors, such as, for example, ascorbic acid and derivatives thereof, aloesin, niacinamide, emblica, elagic acid, liquorice extract, mulberry extract, kojic acid, liquorice extract, rucinol, hydroquinone, azelaic acid, arbutin, magnesium ascorbyl phosphate or the like.
• Preferred examples of compounds having skin-lightening activity are hydroquinone, niacinamide, ascorbic acid and physiologically acceptable salts thereof, kojic acid, arbutin, aloesin, azelaic acid, elagic acid or rucinol.
• Preferred examples of extracts having skin-lightening activity are liquorice extract, mulberry extract or emblica.
• the preparations according to the invention may in addition comprise anti-ageing active compounds, anticellulite active compounds or conventional skin-protecting or skin-care active compounds.
• Skin-protecting or skin-care active compounds can in principle be all active compounds known to the person skilled in the art.
• Particularly preferred anti-ageing active compounds are pyrimidinecarboxylic acids, aryl oximes, bioflavonoids, bioflavonoid-containing extracts, chromones or retinoids.
• Suitable anti-ageing active compounds are preferably also so-called compatible solutes. These are substances which are involved in the osmoregulation of plants or microorganisms and can be isolated from these organisms.
• compatible solutes here also encompasses the osmolytes described in German patent application DE-A-10133202. Suitable osmolytes are, for example, the polyols, methylamine compounds and amino acids and respective precursors thereof.
• Osmolytes in the sense of German patent application DE-A-10133202 are taken to mean, in particular, substances from the group of the polyols, such as, for example, myo-inositol, mannitol or sorbitol, and/or one or more of the osmolytically active substances mentioned below: taurine, choline, betaine, phosphorylcholine, glycerophosphorylcholines, glutamine, glycine, ⁇ -alanine, glutamate, aspartate, proline, and taurine.
• Precursors of these substances are, for example, glucose, glucose polymers, phosphatidylcholine, phosphatidylinositol, inorganic phosphates, proteins, peptides and polyamino acids.
• Precursors are, for example, compounds which are converted into osmolytes by metabolic steps.
• Compatible solutes which are preferably employed in accordance with the invention are substances selected from the group consisting of pyrimidinecarboxylic acids (such as ectoin and hydroxyectoin), proline, betaine, glutamine, cyclic diphosphoglycerate, N-acetylornithine, trimethylamine N-oxide, di-myo-inositol phosphate (DIP), cyclic 2,3-diphosphoglycerate (cDPG), 1,1-diglycerol phosphate (DGP), ⁇ -mannosyl glycerate (firoin), ⁇ -mannosyl glyceramide (firoin-A) or/and dimannosyl diinositol phosphate (DMIP) or an optical isomer, derivative, for example an acid, a salt or ester, of these compounds, or combinations thereof.
• pyrimidinecarboxylic acids such as ectoin and hydroxyectoin
• proline such as
• ectoin ((S)-1,4,5,6-tetrahydro-2-methyl-4-pyrimidinecarboxylic acid) and hydroxyectoin ((S,S)-1,4,5,6-tetrahydro-5-hydroxy-2-methyl-4-pyrimidinecarboxylic acid) and derivatives thereof.
• anti-ageing active compounds which can be used are products from Merck, such as, for example, 5,7-dihydroxy-2-methylchromone, marketed under the trade name RonaCare® Luremine, Ronacare® Isoquercetin, Ronacare® Tilirosid or Ronacare® Cyclopeptide 5.
• chromones for example retinol (vitamin A), retinoic acid, retinaldehyde or also synthetically modified compounds of vitamin A.
• retinoids for example retinol (vitamin A), retinoic acid, retinaldehyde or also synthetically modified compounds of vitamin A.
• the chromones and retinoids described are simultaneously also effective anticellulite active compounds.
• An anticellulite active compound which is likewise known is caffeine.
• the invention likewise relates to a preparation comprising at least one compound of the formula (I), as described above, and one or more self-tanning substances.
• a preparation of this type generally has a contrast-reduction effect and enables a uniform skin shade to be achieved.
• the invention likewise relates to the use of compounds of the formula (I), as described, in combination with one or more self-tanning substances for contrast reduction and achieving a uniform skin shade.
• a contrast-reduction agent is accordingly a substance which reduces a non-uniform skin coloration by reducing the contrast between more strongly and less strongly coloured skin areas. A uneven skin coloration of this type can arise here through non-uniform pigmentation and/or a different distribution of the horny skin.
• Uneven pigmentation is by no means unusual in the population and is based on different levels of melanin production by the melanocytes or an irregular distribution of the melanocytes in the skin.
• the combination of tanning mixtures which are based on the Maillard reaction or Michael addition with melanogenesis-inhibiting substances has the effect that skin areas which are already hyperpigmented lose their high melanin concentration, and the skin shade generated at the skin surface by the colorant becomes established over a large area.
• a contrast reduction can be achieved, in particular, by preparations in which at least one compound of the formula (I) are additionally combined with a self-tanning substance, preferably comprising dihydroxyacetone (DHA) and derivatives derived therefrom, DHA rapid, DHA plus or erythrulose, or a mixture of self-tanning substances, preferably comprising DHA, DHA rapid, DHA plus and/or erythrulose.
• a self-tanning substance preferably comprising dihydroxyacetone (DHA) and derivatives derived therefrom, DHA rapid, DHA plus or erythrulose, or a mixture of self-tanning substances, preferably comprising DHA, DHA rapid, DHA plus and/or erythrulose.
• Advantageous self-tanners which can be employed, inter alia, in a dihydroxyacetone-containing mixture or preparation are: glycerolaldehyde, hydroxymethylglyoxal, ⁇ -dialdehyde, 6-aldo-D-fructose, ninhydrin, 5-hydroxy-1,4-naphtoquinone (juglone) or 2-hydroxy-1,4-naphtoquinone (lawsone) or a mixture of the said compounds.
• Erythrulose is particularly preferably employed in the dihydroxyacetone-containing mixture.
• the at least one compound of the formula (I) can also be used in accordance with the invention together with a mixture of self-tanning substances comprising at least dihydroxyacetone and a further self-tanner selected from the above-mentioned group.
• the mixture to be used in accordance with the invention consists of dihydroxyacetone and at least one further self-tanning substance, as described above.
• This mixture can then be combined in accordance with the invention with at least one compound of the formula (I) and employed in cosmetic, dermatological or pharmaceutical preparations, as described below.
• Dihydroxyacetone or a derivative derived therefrom is very particularly preferably employed without further self-tanning substances.
• coloured pigments may furthermore also be present, where the layer structure of the pigments is not limited.
• the coloured pigment should preferably be skin-coloured or brownish. The selection of a corresponding pigment is familiar to the person skilled in the art.
• compositions or preparations described are particularly suitable for use in the lightening of skin, inhibition of tyrosinase and/or prophylaxis, therapy and/or progress control of pigment disorders of the skin, in all cases in particular in the case of hyperpigmentation, freckles, age spots, sun spots and environmentally induced skin ageing. They are present here in various administration forms which are usually used for this application.
• compositions according to the invention solutions, suspensions, emulsions, PIT emulsions, pastes, ointments, gels, creams, lotions, powders, soaps, surfactant-containing cleansing preparations, oils, aerosols, plasters, compresses, bandages and sprays, in particular for external application.
• Further application forms are, for example, sticks, shampoos and shower baths.
• Typical cosmetic use forms are furthermore also lipsticks, lip-care sticks, powder, emulsion and wax make-up, and sun-protection, pre-sun and after-sun preparations.
• Cosmetic and dermatological preparations according to the invention can be, in particular, a water-free preparation, a lotion or emulsion, such as cream or milk, or microemulsion, in each case of the water-in-oil (W/O) type or of the oil-in-water (O/W) type, a multiple emulsion, for example of the water-in-oil-in-water (W/O/W) type or vice versa (O/W/O), gels or solutions (in particular oily-alcoholic, oily-aqueous or aqueous-alcoholic gels or solutions), a solid stick, an ointment or an aerosol.
• the cosmetic and dermatological preparations according to the invention are applied to the skin in adequate amount in the usual manner for cosmetics.
• An embodiment of the invention is an emulsion which is in the form of a cream or milk and comprises, for example, fatty alcohols, fatty acids, fatty acid esters, in particular triglycerides of fatty acids, lanolin, natural and synthetic oils or waxes and emulsifiers in the presence of water.
• a particularly preferred preparation according to the invention may also be in the form of an alcoholic gel which comprises one or more lower alcohols or polyols, such as ethanol, propylene glycol or glycerol, and a thickener, such as siliceous earth.
• the oily-alcoholic gels additionally comprise natural or synthetic oil or wax.
• the solid sticks preferably consist of natural or synthetic waxes and oils, fatty alcohols, fatty acids, fatty acid esters, lanolin and other fatty substances. If a preparation is formulated as an aerosol, the usual propellants, such as alkanes, air, nitrogen, dinitrogen monoxide, particularly preferably alkanes or air, are preferably used.
• the one or more compounds of the formula (I), as described, can be incorporated into cosmetic or dermatological preparations in the usual manner.
• the preparations may include or comprise, essentially or consist of the said necessary or optional constituents or ingredients. All compounds or components which can be used in the preparations are either known and commercially available or can be synthesised by known processes. Any desired conventional vehicles, assistants and, if desired, further active compounds may be added to the preparation. Preferred assistants originate from the group of the preservatives, stabilisers, solubilisers, colorants, i.e. pigments, dyes, emulsifiers or odour improvers.
• Ointments, pastes, creams and gels may comprise the customary vehicles which are suitable for topical application, such as, for example, animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and titanium dioxide, or mixtures of these substances.
• customary vehicles such as, for example, animal and vegetable fats, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silica, talc and titanium dioxide, or mixtures of these substances.
• Powders and sprays may comprise the customary vehicles, such as, for example, lactose, talc, silica, aluminium hydroxide, calcium silicate and polyamide powder, or mixtures of these substances.
• Sprays may additionally comprise the customary readily volatile, liquefied propellants, such as, for example, chlorofluorocarbons, propane/butane or dimethyl ether.
• Compressed air can also advantageously be used. However, air can also be employed in pressureless metering devices, such as, for example, pump sprays.
• Solutions and emulsions may comprise the customary vehicles, such as solvents, solubilisers and emulsifiers, such as, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils, in particular cottonseed oil, peanut oil, wheatgerm oil, olive oil, castor oil and sesame oil, glycerol fatty acid esters, polyethylene glycols and fatty acid esters of sorbitan, or mixtures of these substances.
• solvents such as solvents, solubilisers and emulsifiers, such as, for example, water, ethanol, isopropanol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butyl glycol, oils, in particular cottonseed oil
• a preferred solubiliser in general is 2-isopropyl-5-methylcyclohexanecarbonyl-D-alanine methyl ester.
• Suspensions may comprise the customary vehicles, such as liquid diluents, such as, for example, water, ethanol or propylene glycol, suspension media, such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.
• liquid diluents such as, for example, water, ethanol or propylene glycol
• suspension media such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol esters and polyoxyethylene sorbitan esters, microcrystalline cellulose, aluminium metahydroxide, bentonite, agar-agar and tragacanth, or mixtures of these substances.
• Soaps may comprise the customary vehicles, such as alkali-metal salts of fatty acids, salts of fatty acid monoesters, fatty acid protein hydrolysates, isothionates, lanolin, fatty alcohol, vegetable oils, plant extracts, glycerol, sugars, or mixtures of these substances.
• customary vehicles such as alkali-metal salts of fatty acids, salts of fatty acid monoesters, fatty acid protein hydrolysates, isothionates, lanolin, fatty alcohol, vegetable oils, plant extracts, glycerol, sugars, or mixtures of these substances.
• Surfactant-containing cleansing products may comprise the customary vehicles, such as salts of fatty alcohol sulfates, fatty alcohol ether sulfates, sulfosuccinic acid monoesters, fatty acid protein hydrolysates, isothionates, imidazolinium derivatives, methyl taurates, sarcosinates, fatty acid amide ether sulfates, alkylamidobetaines, fatty alcohols, fatty acid glycerides, fatty acid diethanolamides, vegetable and synthetic oils, lanolin derivatives, ethoxylated glycerol fatty acid esters, or mixtures of these substances.
• Face and body oils may comprise the customary vehicles, such as synthetic oils, such as fatty acid esters, fatty alcohols, silicone oils, natural oils, such as vegetable oils and oily plant extracts, paraffin oils, lanolin oils, or mixtures of these substances.
• the preferred preparation forms according to the invention include, in particular, emulsions. O/W emulsions are particularly preferred. Emulsions, W/O emulsions and O/W emulsions can be obtained in a conventional manner. Emulsions according to the invention are advantageous and comprise, for example, the said fats, oils, waxes and other fatty substances, as well as water or an aqueous phase, for example with solvents or hydrophilic surfactants, and an emulsifier, as usually used for a preparation of this type.
• the oil phase of the emulsions, oleogels or hydrodispersions or lipodispersions is advantageously selected from the group of esters of saturated and/or unsaturated, branched and/or unbranched alkanecarboxylic acids having a chain length of 3 to 30 C atoms and saturated and/or unsaturated, branched and/or unbranched alcohols having a chain length of 3 to 30 C atoms, from the group of the esters of aromatic carboxylic acid and saturated and/or unsaturated, branched and/or unbranched alcohols having a chain length of 3 to 30 C atoms.
• Ester oils of this type can then advantageously be selected from the group isopropyl myristate, isopropyl palmitate, isopropyl stearate, isopropyl oleate, n butyl stearate, n-hexyl laurate, n-decyl oleate, isooctyl stearate, isononyl stearate, isononyl isononanoate, 2-ethylhexyl palmitate, 2-ethylhexyl laurate, 2-hexyldecyl stearate, 2-octyldodecyl palmitate, oleyl oleate, oleyl erucate, erucyl oleate, erucyl erucate and synthetic, semi-synthetic and natural mixtures of esters of this type, such as, for example, jojoba oil.
• the oil phase can advantageously be selected from the group of branched and unbranched hydrocarbons and hydrocarbon waxes, silicone oils, dialkyl ethers, the group of saturated or unsaturated, branched or unbranched alcohols, and fatty acid triglycerides, specifically the triglycerol esters of saturated and/or unsaturated, branched and/or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12-18 C atoms.
• the fatty acid triglycerides can advantageously be selected, for example, from the group of synthetic, semi-synthetic and natural oils, for example olive oil, sunflower oil, soya oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil and the like. Any desired mixtures of oil and wax components of this type may also advantageously be employed for the purposes of the present invention. It may also be advantageous to employ waxes, for example cetyl palmitate, as sole lipid component of the oil phase.
• synthetic, semi-synthetic and natural oils for example olive oil, sunflower oil, soya oil, peanut oil, rapeseed oil, almond oil, palm oil, coconut oil, palm kernel oil and the like.
• Any desired mixtures of oil and wax components of this type may also advantageously be employed for the purposes of the present invention. It may also be advantageous to employ waxes, for example cetyl palmitate, as sole lipid component of the oil phase.
• the aqueous phase of the preparations according to the invention optionally advantageously comprises alcohols, diols or polyols having a low carbon number, and ethers thereof, preferably ethanol, isopropanol, propylene glycol, glycerol, ethylene glycol, ethylene glycol monoethyl or monobutyl ether, propylene glycol monomethyl, monoethyl or monobutyl ether, diethylene glycol monomethyl or monoethyl ether and analogous products, furthermore alcohols having a low carbon number, such as, for example, ethanol, isopropanol, 1,2-propanediol, glycerol, and, in particular, one or more thickeners, which may advantageously be selected from the group of silicon dioxide, aluminium silicates, polysaccharides or derivatives thereof, such as, for example, hyaluronic acid, xanthan gum, hydroxypropylmethylcellulose, particularly advantageously from the group of the polyacrylates,
• the preparations according to the invention comprise hydrophilic surfactants.
• the hydrophilic surfactants are preferably selected from the group of the alkylglucosides, acyl lactylates, betaines and coconut amphoacetates.
• Emulsifiers that can be used are, for example, the known W/O and O/W emulsifiers. It is advantageous to use further conventional co-emulsifiers in the preferred O/W emulsions according to the invention.
• the co-emulsifiers selected in accordance with the invention are advantageously, for example, O/W emulsifiers, principally from the group of substances having HLB values of 11-16, very particularly advantageously having HLB values of 14.5-15.5, so long as the O/W emulsifiers have saturated radicals R and R′. If the O/W emulsifiers have unsaturated radicals R and/or R′, or if isoalkyl derivatives are present, the preferred HLB value of such emulsifiers may also be lower or higher.
• fatty alcohol ethoxylates from the group of the ethoxylated stearyl alcohols, cetyl alcohols, cetylstearyl alcohols (cetearyl alcohols).
• An ethoxylated alkyl ether carboxylic acid or salt thereof which can advantageously be used is sodium laureth-11 carboxylate.
• An alkyl ether sulfate which can advantageously be used is sodium laurethyl-4 sulfate.
• An ethoxylated cholesterol derivative which can advantageously be used is polyethylene glycol (30) cholesteryl ether. Polyethylene glycol (25) soyasterol has also proven successful.
• Ethoxylated triglycerides which can advantageously be used are the polyethylene glycol (60) evening primrose glycerides.
• polyethylene glycol glycerol fatty acid esters from the group of polyethylene glycol (20) glyceryl laurate, polyethylene glycol (21) glyceryl laurate, polyethylene glycol (22) glyceryl laurate, polyethylene glycol (23) glyceryl laurate, polyethylene glycol (6) glyceryl caprate/cprinate, polyethylene glycol (20) glyceryl oleate, polyethylene glycol (20) glyceryl isostearate, polyethylene glycol (18) glyceryl oleate (cocoate).
• sorbitan esters from the group polyethylene glycol (20) sorbitan monolaurate, polyethylene glycol (20) sorbitan monostearate, polyethylene glycol (20) sorbitan monoisostearate, polyethylene glycol (20) sorbitan monopalmitate and polyethylene glycol (20) sorbitan monooleate.
• fatty alcohols having 8 to 30 carbon atoms monoglycerol esters of saturated and/or unsaturated, branched and/or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 C atoms, diglycerol esters of saturated and/or unsaturated, branched and/or unbranched alkanecarboxylic acids having a chain length of 8 to 24, in particular 12 to 18 C atoms, monoglycerol ethers of saturated and/or unsaturated, branched and/or unbranched alcohols having a chain length of 8 to 24, in particular 12 to 18 C atoms, diglycerol ethers of saturated and/or unsaturated, branched and/or unbranched alcohols having a chain length of 8 to 24, in particular 12 to 18 C atoms, propylene glycol esters of saturated and/or unsaturated,
• W/O emulsifiers are glyceryl monostearate, glyceryl monoisostearate, glyceryl monomyristate, glyceryl monooleate, diglyceryl monostearate, diglyceryl monoisostearate, propylene glycol monostearate, propylene glycol monoisostearate, propylene glycol monocaprylate, propylene glycol monolaurate, sorbitan monoisostearate, sorbitan monolaurate, sorbitan monocaprylate, sorbitan monoisooleate, sucrose distearate, cetyl alcohol, stearyl alcohol, arachidyl alcohol, behenyl alcohol, isobehenyl alcohol, selachyl alcohol, chimyl alcohol, polyethylene glycol (2) stearyl ether (steareth-2), glyceryl monolaurate, glyceryl monocaprinate, glyceryl monocaprylate or PEG-30
• the preparation may comprise cosmetic adjuvants which are usually used in this type of preparation, such as, for example, thickeners, softeners, moisturisers, surface-active agents, emulsifiers, preservatives, antifoams, perfumes, waxes, lanolin, propellants, dyes and/or pigments, which colour the composition itself or the skin, and other ingredients usually used in cosmetics.
• cosmetic adjuvants which are usually used in this type of preparation, such as, for example, thickeners, softeners, moisturisers, surface-active agents, emulsifiers, preservatives, antifoams, perfumes, waxes, lanolin, propellants, dyes and/or pigments, which colour the composition itself or the skin, and other ingredients usually used in cosmetics.
• the dispersant or solubiliser used can be an oil, wax or other fatty substances, a lower monoalcohol or a lower polyol or mixtures thereof.
• Particularly preferred monoalcohols or polyols include ethanol, i-propanol, propylene glycol, glycerol and sorbitol.
• the invention also relates to a process for the preparation of a preparation according to the invention, characterised in that the at least one compound of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios, are mixed with at least one vehicle which is suitable for topical applications and optionally with physiologically acceptable assistants and/or fillers.
• the process for the preparation typically comprises the following steps: (a) mixing of at least one compound of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios, with at least one further active compound and at least one vehicle which is suitable for topical applications and optionally with physiologically acceptable assistants and/or fillers, and optionally (b) apparent making-ready of the compounds of the formula (I).
• the preparations according to the invention can be prepared with the aid of techniques which are well known to the person skilled in the art.
• the mixing can result in dissolution, emulsification or dispersal of the at least one compound of the formula (I), as described above, in the vehicle.
• the prior teaching of the invention and embodiments thereof relating to the compounds of the formula (I) and preparations therewith is valid and can be applied without restrictions to the preparation of the preparation, if it appears appropriate.
• the apparent making-ready is directed to the use in the sense of the invention, i.e. for the use in the lightening of skin, for the use in the inhibition of tyrosinase, for the use in the prophylaxis, therapy and/or progress control of pigment defects of the skin and/or for the reduction of contrast differences in skin shade which are caused by areas pigmented to different extents.
• the apparent or appropriate making-ready can consist, for example, in: a) particular arrangement of the substance or matter, i.e.
• the present invention furthermore additionally relates to compounds of the formula of the formula (I)
• R1 and R2 are selected, independently of one another, from:
• the preparation of these compounds can be carried out by esterification of dihydroxyfumaric acid by standard esterification methods which are familiar to the person skilled in the art.
• the present invention therefore furthermore also relates to a process for the preparation of compounds of the formula (I) as described above in which the carboxylic acid functionalities of dihydroxyfumaric acid are esterified using compounds of the formula R1-OH and R2-OH.
• the compounds of the formula (I) as defined above are particularly suitable for use in the lightening of skin, inhibition of tyrosinase, and/or prophylaxis, therapy and/or progress control of pigment disorders of the skin.
• These compounds can, in particular, also be combined with self-tanning substances which are based on the principle of the generation of coloured pigments by non-enzymatic tanning reaction of the self-tanning substances with keratin-containing matrices, so that a more uniform skin shade is achieved.
• the prior teaching of the invention and embodiments thereof relating to the use of compounds of the formula (I) and preparation thereof applies.
• Another embodiment of the present invention relates to a medicament comprising at least one compound of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios.
• a “drug”, “medicament” and a “pharmaceutical composition”, “pharmaceutical formulation” or “pharmaceutical preparation” here is any composition which can be employed in the prophylaxis, therapy, progress control or aftertreatment of patients who, at least temporarily, exhibit a pathogenic modification of the overall condition or the condition of individual parts of the patient organism, preferably as a consequence of pigment disorders of the skin.
• any substance which facilitates, enhances or modifies an effect with the compounds in accordance with the invention is an “adjuvant”.
• adjuvants are, for example, aluminium compounds, such as, for example, aluminium hydroxide or aluminium phosphate, saponins, such as, for example, QS 21, muramyl dipeptide or muramyl tripeptide, proteins, such as, for example, gamma-interferon or TNF, MF 59, phosphatdibylcholine, squalene or polyols.
• DNA which encodes a protein with an adjuvant effect can be applied in parallel or in a construct.
• the introduction of the pharmaceutical composition into a cell or organism can be carried out in accordance with the invention in any manner which enables tyrosinase to be brought into contact with the compounds present in the composition and as a consequence of which a response to be induced.
• the pharmaceutical composition of the present invention can be administered orally, topically, transdermally, transmucosally, transurethrally, vaginally, rectally, pulmonarily, enterally and/or parenterally, preferably topically or transdermally.
• the type of administration selected depends on the indication, the dose to be administered, individual-specific parameters, etc. In particular, the various types of administration facilitate site-specific therapy, which minimises side effects and reduces the active-compound dose.
• compositions are prepared corresponding to the desired type of administration in a suitable dosage and in a manner known per se using the customary solid or liquid vehicles and/or diluents and the assistants usually employed.
• pharmaceutically acceptable excipients known to the person skilled in the art can basically form part of the pharmaceutical composition according to the invention, where the amount of excipient material which is combined with the active compound in order to prepare a single dose varies depending on the individual to be treated and the type of administration.
• pharmaceutically tolerated additives include salts, buffers, fillers, stabilisers, complexing agents, antioxidants, solvents, binders, lubricants, tablet coatings, flavours, dyes, preservatives, adjusters and the like.
• excipients of this type are water, vegetable oils, benzyl alcohols, alkylene glycol, polyethylene glycol, glycerol triacetate, gelatine, carbohydrates, such as, for example, lactose or starch, magnesium stearate, talc and Vaseline.
• the pharmaceutical formulation can be in the form of a tablet, film tablet, dragee, lozenge, capsule, pill, powder, granules, syrup, juice, drops, solution, dispersion, suspension, suppository, emulsion, implant, cream, gel, ointment, paste, lotion, serum, oil, spray, aerosol, adhesive, plaster or bandage.
• Oral administration forms which are prepared are preferably tablets, film tablets, dragees, lozenges, capsules, pills, powders, granules, syrups, juices, drops, solutions, dispersions or suspensions—including as depot form.
• parenteral medicament forms such as, for example, suppositories, suspensions, emulsions, implants or solutions
• the medicament active compound is formulated in a conventional manner with at least one pharmaceutically acceptable vehicle, such as, for example, microcrystalline cellulose, and optionally further assistants, such as, for example, moisturisers, to give solid formulations which can be applied to the skin, such as, for example, creams, gels, ointments, pastes, powders or emulsions, or to give liquid formulations which can be applied to the skin, such as, for example, solutions, suspensions, lotions, sera, oils, sprays or aerosols.
• pharmaceutically acceptable vehicle such as, for example, microcrystalline cellulose
• further assistants such as, for example, moisturisers
• the pharmaceutical composition is preferably in a form for topical application.
• the pharmaceutical composition may also be in the form of a solid composition, for example in the lyophilised state, and can then be prepared before use by addition of a dissolving agent, such as, for example, distilled water.
• a dissolving agent such as, for example, distilled water.
• the person skilled in the art is familiar with the basic principles of the preparation of lyophilisates.
• the concentration of the active compound in the formulation can be 0.01 to 100 percent by weight. It is crucial that the pharmaceutical composition comprises, as active compound, an effective amount of the compound together with the pharmaceutically tolerated assistants.
• the terms “effective amount” or “effective dose” are used interchangeably herein and denote an amount of the pharmaceutical active compound which has a prophylactically or therapeutically relevant effect on a disease or pathological change in cell, tissue, organ or mammal.
• a “prophylactic effect” prevents the outbreak of a disease and also includes an increase in normal physiological function. Prophylaxis is advisable, in particular, if an individual has predispositions for the onset of the above-mentioned diseases, such as, for example, a family history, a gene defect or a recently survived disease.
• a “therapeutically relevant effect” results in part or full freedom from one, more than one or all disease symptoms or results in the partial or complete return of one, more than one or all physiological or biochemical parameters which are associated with or causally involved in the disease or pathological change to the normal state.
• Progress control is also taken to be a type of therapeutic treatment if the compounds are administered at certain intervals, for example in order completely to eliminate the symptoms of a disease.
• the respective dose or dose range for the administration of the compounds according to the invention is sufficiently large to achieve the desired prophylactic or therapeutic effect of induction of a biological or medical response. In general, the dose will vary with the age, constitution and gender of the patient, and the severity of the disease will be taken into account.
• the specific dose, frequency and duration of administration are, in addition, dependent on a multiplicity of factors, such as, for example, the targeting and bonding ability of the compounds, feeding habits of the individual to be treated, type of administration, excretion rate and combination with other drugs.
• the individual dose can be adjusted both with respect to the primary disease and also with respect to the occurrence of any complications.
• the precise dose can be established by a person skilled in the art using known means and methods.
• the compounds are administered in a dose of 0.01 mg to 1 g per dosage unit, preferably between 1 to 700 mg, particularly preferably 5 to 100 mg.
• the daily dose is in particular between 0.02 and 100 mg/kg of body weight.
• the pharmaceutical composition may, in an embodiment of the invention, also comprise one or more further active compounds, where simultaneous or successive administration is conceivable.
• the therapeutic effect of the pharmaceutical composition according to the invention can consist, for example, in certain skin lighteners having a better action through the inhibition of tyrosinase as a desired side effect or in the number of side effects of these drugs being reduced by the reduction in the dose.
• the invention furthermore teaches a method for the prophylaxis, therapy and/or progress control of pigment disorders of the skin in which an effective amount of at least one compound of the formula (I) and/or physiologically acceptable salts, tautomers and/or solvates thereof, including mixtures thereof in all ratios, is administered to a subject to be treated.
• Preferred subjects in the sense of the invention are humans or animals, particularly preferably humans. It is known to the person skilled in the art here that he can administer the above-mentioned compounds of the invention, which can of course also be used as the pharmaceutical composition, in various doses to an organism, in particular a human patient.
• the effective amount and the type of administration can be determined by the person skilled in the art by routine experiments.
• the prior teaching of the invention and embodiments thereof are valid and can be applied without restrictions to the treatment method, if it appears appropriate.
• dihydroxyfumaric acid derivatives of the formula (I) were provided.
• the compounds of the formula (I) and derivatives thereof are distinguished by high specificity and stability and easy handling. These properties form the basis for a reproducible mode of action and reliable and safe interaction with the corresponding target structures.
• the invention also includes the use of the present dihydroxyfumaric acid derivatives of the formula (I) for the inhibition, regulation and/or modulation of the signalling cascade of tyrosinase and thus offers novel tools for research and/or diagnostics.
• compositions which comprise the said compounds and the use of these compounds for the treatment of tyrosinase-promoted disorders are a highly promising approach for achieving direct and immediate alleviation of symptoms in humans and animals. This is particularly advantageous for effective treatment of pigment disorders, either as monotherapy or in combination with other skin-lightening therapies.
• the control of skin pigmentation is likewise a central topic of modern cosmetic products. Whether a very pale or rather a tanned appearance is preferred is crucially dependent on cultural factors. Products which serve for skin lightening are, for example, of particular interest in the Asian culture area, where a pale skin shade is associated with a raised social position and financial wealth.
• the compounds of the formula (I) can, in accordance with the invention, be administered in considerably lower concentration, while they achieve similar or even superior biological efficacy compared with the less-potent skin-lightening substances of the prior art. They advantageously exhibit a high and long-lasting activity with respect to their action as skin-lightening active compounds.
• the active compounds according to the invention are distinguished not only by improved efficacy, but also by use safety and good formulation ability. Thus, they can easily be incorporated into preparations and have increased stability in the preparations.
• B16V mouse melanoma cells (manufacturer: DSMZ; Article No.: ACC370) are transferred into RPMI medium (Invitrogen, Article No.: 31870), to which 10% of FBS (foetal bovine serum; Invitrogen, Article No.: 10499044), 2 mM L-glutamine (Invitrogen, Article No: 25030) and 1 mM sodium pyruvate (Invitrogen, Article No.: 11360) had additionally been added, and incubated at 37° C. and 5% CO 2 for 72 h.
• the medium is separated off, and the cells are washed once with 10 ml of DPBS (Dulbecco's phosphate-buffered salines; Invitrogen, Article No.: 14190), and the medium is subsequently removed by suction.
• 1 ml of HyQtase cell detachment solution (Hyclone, Article No.: SV30030.01) is added to the cells.
• the bottle is swirled a number of times, and the HyQtase cell detachment solution is subsequently removed by suction.
• the cells are then incubated in the incubator at 37° C. and 5% CO 2 for 5 min.
• the cells are taken up in the modified RPMI medium (see above), and the cell count is determined.
• the cells are stained with Trypan Blue and counted in a Neubauer counting chamber.
• the cells are subsequently sown out again in the modified RPMI medium (see above) in a defined cell count of 80,000 cells per well (6-well clear plate, TCT, PS (Nunc)).
• the cells are incubated at 37° C. and 5% CO 2 for 24 h, the medium is then removed. 1980 ⁇ l of the dilution of the respective substance to be tested are subsequently added.
• the substance is dissolved in DMSO and subsequently filtered through a sterile filter (0.2 ⁇ m, Millipore, Article No. SLLG013SL).
• the solution is then diluted with the modified RPMI medium (see above, but in this case the FBS content is only 5%) in such a way that the final concentration of the substance dilution has the desired final concentration as shown in Table 1.
• alpha-MSH solution alpha-melanocyte-stimulating hormone, DMSO, Sigma, Article No.: D2650
• the medium is removed by suction, and the cells are washed with 1000 ⁇ l of DPBS (Invitrogen, Article No.: 14190). The medium is again removed by suction. 25011 of HyQtase cell detachment solution (Hyclone, Article No.: SV30030.01) are added to the cells. The 6-well plate is swirled a number of times, and the HyQtase cell detachment solution is subsequently removed by suction. The cells are then incubated in the incubator at 37° C. and 5% CO 2 for 5 min.
• HyQtase cell detachment solution Hyclone, Article No.: SV30030.01
• the cells are taken up in 1.5 ml of DPBS (Invitrogen, Article No.: 14190) and transferred into a cup (SARSTEDT, Ref. 72.692.005). The cell count is subsequently determined. To this end, the cells are stained with Trypan Blue and counted in a Neubauer counting chamber. The cells centrifuged for 1 min at 3500 g. The pellets obtained are photographed, and the supernatant is subsequently removed by suction. The pellets are dissolved in 1 ml of 1N NaOH at 80° C. for 1 h and then cooled to RT.
• the skin-lightening effect of dihydroxyfumaric acid is surprisingly also higher compared with the hydroxy acids lactic acid and glycolic acid disclosed in WO 01/66105 A1, which are employed therein as skin-lightening substances in combination with kojic acid and an antioxidant.
• phase B To 80° C. With stirring, slowly introduce phase B into phase A. Homogenise. Allow to cool with constant stirring and add phase C at 40° C.

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